Herpes Simplex Virus Colitis After Treatment With Upadacitinib

Background:
JAK inhibitors are known to increase the risk of herpes virus infections, most commonly herpes zoster. Although less frequently reported, reactivation of herpes simplex virus (HSV) can occur. We present a case of a patient with newly diagnosed Crohn’s disease who, after being treated with Upadacitinib, developed HSV-associated colonic perforation.
Methods:
A 60-year-old female without pertinent past medical history presented with lower abdominal pain, hematochezia, and 10-12 episodes of watery diarrhea for 3 weeks. She denied recent travel or infectious symptoms. She was diagnosed with acute infectious colitis and started on IV metronidazole and levofloxacin. Her symptoms failed to improve, and a colonoscopy revealed severe ulceration throughout with skip lesions, inflammation, and a possible fistula. Biopsies confirmed Crohn’s disease. Despite starting IV steroids, her symptoms worsened and she required admission to the intensive care unit for hemorrhagic shock. After a shared decision-making conversation, she opted for treatment with medical therapy and was started on Upadacitinib 45 mg daily for severe colitis. Her abdominal pain and stool frequency improved. Shortly before discharge, she developed a fever and worsening inflammatory markers. A CT scan of the abdomen and pelvis revealed massive pneumoperitoneum, necessitating urgent laparoscopic hand-assisted total abdominal colectomy for bowel perforation. Upadacitinib was discontinued post-operatively. Seven days after colectomy, the patient developed cutaneous and ocular lesions which were confirmed as HSV-2 through cultures from her eye. Pathological examination of the colectomy specimen revealed HSV in the serosa and deep submucosa. HSV colitis was suspected to have contributed to her bowel perforation. She was treated with 22 days of acyclovir, leading to resolution of her cutaneous lesions. Unfortunately, she has continued to deteriorate with polymicrobial intra-abdominal abscesses requiring percutaneous drains and severe malnutrition despite total parenteral nutrition.
Conclusions:
Despite the high prevalence of HSV in the general population, herpes simplex colitis is rare. It may occur in patients with inflammatory bowel disease or those on immunosuppressive medications. JAK inhibitors, including Upadacitinib, are associated with an increased risk of herpetic infections, typically herpes zoster. Trials have shown herpes zoster infection is more frequent with Upadacitinib compared to other selective JAK1 inhibitors and biologic classes. HSV infection in patients on Upadacitinib have been reported less frequently, however given the similar mechanisms of viral infection of HSV and VZV, the risk of HSV reactivation may parallel that of VZV. This case illustrates a patient with severe Crohn’s disease who, after being treated with Upadacitinib, developed disseminated HSV with ocular, cutaneous, and colonic involvement. Her course was complicated by bowel perforation and need for colectomy, thought to be attributed to both severe Crohn’s disease and acute HSV colitis. Clinicians should be aware of the increased risk of herpetic reactivation with Upadacitinib and evaluate a patient’s individualized risk before initiating JAK inhibitors. Patients with known HSV on immunosuppressive therapy should be closely monitored for complications and be appropriately vaccinated against indicated infectious diseases.